Alzheimer's disease (“AD”) is a neurodegenerative illness characterized by memory loss and other cognitive deficits. AD is the most common form of dementia and affects one in every eight people over the age of 65 and one in every two over the age of 85. AD is the sixth leading cause of death in the United States. Over 5.5 million Americans suffer from AD, with an estimated annual cost of $200 billion USD. By 2050, it is projected that AD will affect over 20 million Americans at an annual price tag of $1.1 Trillion USD (in 2011 dollars). Around the world, the estimated figures for the year 2011 were over 37 million sufferers, at an associated cost of over $600 billion (USD).
Effective diagnostic tests for AD are needed in the field. At present, AD is typically only conclusively diagnosed by post-mortem histopathological analysis. Diagnosis in living subjects relies primarily on psychiatric testing to detect cognitive impairment. However, the major neuropathological hallmarks of AD—extracellular amyloid-β (“Aβ”) plaque deposits and intracellular neurofibrillary tangles—manifest long before clinical symptoms are discernable. Aβ deposits also represent a major risk factor for hemorrhagic stroke.
Two positron emission tomography (PET) imaging agents that bind specifically to amyloid plaques have recently been approved by the FDA, and can be used for the detection of amyloid plaques. However, their spatial resolution is limited by that of the PET modality, and is on the order of 5-10 mm, limiting any anatomy-specific information available in the image. PET imaging also requires the use of radio-isotopes, and carries the risk of significant radiation: an amyloid scan is estimated to expose the patient to about 7 mSv of radiation dose, roughly equivalent to several CT scans, as a typical head CT may be about 2 mSv. Availability of radioactive PET agents also remains a challenge, due to their short half-life. Simultaneous detection of a cognate factor such as tau tangles could improve the specificity of a diagnostic test, and a number of PET imaging agents for tau detection are currently in development. A non-radioactive amyloid imaging agent would be of significant interest, addressing both the distribution challenges and the radiation dose concerns with current PET imaging agents, and in combination with a tau imaging agent, possibly constituting a diagnostic for AD.
Some previous efforts on developing non-radioactive amyloid-targeting MRI agent have primarily focused on either proton T2 (using the T2 relaxivities of iron oxide nanoparticles), or 19F imaging (using high signal-to-noise ratios achievable due to the absence of endogenous F signal). High T2 relaxivities lead to the suppression of overall signal, making detection and differentiation from inherent hypo-intense regions challenging, and quantitation of the images unreliable. Further, the absence of endogenous MR-visible fluorine also means there is no anatomical landmark in the 19F image.
Other previous work demonstrated that liposomes targeted to amyloid plaque by the thioflavine analog Methoxy-XO4, penetrated the blood-brain barrier (BBB), and successfully bound the majority of amyloid plaques in the APP/PSEN1 mouse model of AD. Existing amyloid binding ligands, including methoxy-XO4 are, however, hydrophobic. In liposomal formulations, they interfere with the lipid bilayer. When loaded with Gd chelates for MRI T1 contrast, methoxy-XO4 targeted liposomes were unstable to the osmotic gradient created by the high Gd chelate internal concentration, and were destabilized.
The present application appreciates that detecting amyloid deposits may be a challenging endeavor.